After focal cerebral ischemia, the infarct volume increases rapidly within acute infarct expansion (initial 12 to 24 h) and continues slowly during delayed infarct expansion (25 to 168 h). While acute infarct expansion represents progressive necrosis within the ischemic core, delayed infarct expansion starts as disseminated apoptotic cell death in a narrow rim surrounding the infarct border, which gradually coalesces to form a larger infarct. Discovery of a distinct correlation between reactive astrogliosis along the infarct border and delayed infarct expansion in the rodent ischemia model led us to investigate the possible causal relationship between the two events. Specifically, the calcium binding protein S100B exerts detrimental effects on cell survival through activation of various intracellular signaling pathways, resulting in altered protein expression. Arundic acid [(R)-(-)-2-propyloctanoic acid, ONO-2506] is a novel agent that inhibits S100B synthesis in cultured astrocytes. In the rodent ischemia model, this agent was shown to inhibit both the astrocytic overexpression of S100B and the subsequent activation of signaling pathways in the peri-infarct area. Concurrently, delayed infarct expansion was prevented, and neurologic deficits were promptly ameliorated. The results of subsequent studies suggest that the efficacy of arundic acid is mediated by restoring the activity of astroglial glutamate transporters via enhanced genetic expression.

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1 Desensitization of m-and k-opioid receptor-mediated inhibition of voltage-dependent Ca 2+ channels was studied in a Xenopus oocyte translation system. 2 In the oocytes coexpressing k-opioid receptors with Nor Q-type Ca 2+ channel a 1 and b subunits, the k-agonist, U50488H, inhibited both neuronal Ca 2+ channel current responses in a pertussis toxin-sensitive manner and the inhibition was reduced by prolonged agonist exposure. 3 More than 10 min was required to halve the inhibition of Q-type channels by the k-agonist. However, the half-life for the inhibition of N-type channels was only 6+1 min. In addition, in the oocytes coexpressing m-opioid receptors with N-type or Q-type channels, the uncoupling rate of the m-receptor-mediated inhibition of N-channels was also faster than that of Q-type channels. 4 In the oocytes coexpressing both m-and k-receptors with N-type channels, stimulation of either receptor resulted in a cross-desensitization of the subsequent response to the other agonist. Treatment of oocytes with either H-8 (100 mM), staurosporine (400 nM), okadaic acid (200 nM), phorbol myristate acetate (5 nM) or forskolin (50 mM) plus phosphodiesterase inhibitor did not a€ect either the desensitization or the agonist-evoked inhibition of Ca 2+ channels. 5 These results suggest that the rate of rapid desensitization is dependent on the a 1 subtype of the neuronal Ca 2+ channel, and that a common phosphorylation-independent mechanism underlies the heterologous desensitization between opioid receptor subtypes.